Ghrelin in Chronic Kidney Disease

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cachexia, renal osteodystrophy, and increased cardiovascular risk in CKD. Ghrelin is a gastric hormone. The biological effects of ghrelin are mediated through ...

Hindawi Publishing Corporation International Journal of Peptides Volume 2010, Article ID 567343, 7 pages doi:10.1155/2010/567343

Review Article Ghrelin in Chronic Kidney Disease Wai W. Cheung and Robert H. Mak Division of Pediatric Nephrology, Department of Pediatrics, University of California San Diego, 9500 Gilman Drive, Mail code no. 0634, La Jolla, CA 92093-0634, USA Correspondence should be addressed to Robert H. Mak, [email protected] Received 14 November 2009; Accepted 8 February 2010 Academic Editor: Hubert Vaudry Copyright © 2010 W. W. Cheung and R. H. Mak. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Patients with chronic kidney disease (CKD) often exhibit symptoms of anorexia and cachexia, which are associated with decreased quality of life and increased mortality. Chronic inflammation may be an important mechanism for the development of anorexia, cachexia, renal osteodystrophy, and increased cardiovascular risk in CKD. Ghrelin is a gastric hormone. The biological effects of ghrelin are mediated through the growth hormone secretagogue receptor (GHSR). The salutary effects of ghrelin on food intake and meal appreciation suggest that ghrelin could be an effective treatment for anorexic CKD patients. In addition to its appetitestimulating effects, ghrelin has been shown to possess anti-inflammatory properties. The known metabolic effects of ghrelin and the potential implications in CKD will be discussed in this review. The strength, shortcomings, and unanswered questions related to ghrelin treatment in CKD will be addressed.

1. Introduction The cachexia syndrome in patients with chronic kidney disease (CKD) consists of muscle wasting, anorexia, and increased elevated energy expenditure. Cachexia is an important risk factor for mortality in patients with CKD, which is 100-fold to 200-fold higher than in the general population. Cachexia, a common feature in many chronic inflammatory diseases, is distinct from malnutrition, which is defined as the consequence of insufficient nutrients [1]. Responses in malnutrition are adaptive, whereas those in cachexia are maladaptive. In malnutrition, such as in simple starvation, fats are preferentially utilized and lean body mass is preserved. In cachexia, muscle mass is wasted and fats are relatively underutilized. Anorexia, defined as the loss of desire for food, is prevalent in patients CKD. Anorexia in CKD patients can arise from decreased taste and smell of food, early satiety, dysfunctional hypothalamic membrane adenylate cyclase, increased brain tryptophan, and increased cytokine production. Anorexia reduces oral energy and protein intakes and contributes to the development of cachexia. Elevated resting energy expenditure was associated with increased mortality and cardiovascular death in CKD and was closely correlated with the prevalence of cachexia

among these patients [2]. To date, there is no effective therapy for cachexia in CKD. Nutritional strategies such as caloric supplementation and appetite stimulants have been largely unsuccessful. Thus, there is an urgent need for the development of new therapeutic agents for this potentially fatal complication of CKD [3].

2. Energy Metabolism in CKD New insights into the pathophysiolgy of cachexia in CKD hold the promise of novel therapeutic strategies. One important mechanism for cachexia in CKD is that elevated circulating proinflammatory cytokines act on CNS and regulate the release and function of a number of key neuropeptides, thereby influence energy metabolism. Leptin and central melanocortin systems have been suggested as targets of cytokine action in the hypothalamus, which is a critical regulator of food intake and energy homeostasis [4]. There are two distinct subsets of neurons that control food intake in the hypothalamus. One subset of neurons produce neuropeptide Y (NPY) that stimulates food intake while an adjacent neuronal subset produces melanocortin peptides, which inhibit eating. Circulating leptin and insulin decrease

2 appetite by inhibiting NPY and agouti-related peptide (AgRP), while stimulating the production of melanocortin peptides in the hypothalamus. Inflammatory cytokines induce anorexia by their central actions. Cytokines regulate gastrointestinal activities, cause metabolic changes, affect the endocrine system, and modulate the neuropeptide profile of the hypothalamus, all of which can influence eating behavior [1, 5]. We have demonstrated that cachexia in a mouse model of CKD could be ameliorated by genetic or pharmacological blockade of leptin and central melanocortin signaling via the melanocortin receptor type-4 (MC4-R) [6]. However, potential clinical utility of this approach is limited by the need to deliver AgRP intracerebroventricularly. We then examined the effects of NBI-12i, a small molecule MC4R reverse agonist, in a mouse model of uremic cachexia. Intraperitoneal injection of NBI-12i ameliorated uremic cachexia. The protective effects of NBI-12i may be due to the normalization of the upregulation of uncoupling protein expression seen in CKD mice [7]. These data underscore the importance of melanocortin signaling in the pathogenesis of uremic cachexia and demonstrate the potential utility of MC4-R antagonists as a novel therapeutic approach.

3. Ghrelin Physiology Ghrelin is a gut peptide that stimulates the production of growth hormone (GH) from the pituitary gland [8]. Ghrelin, a natural ligand of the GH secretagogue receptor 1a (GHS-R1a), is secreted into the bloodstream primarily from the stomach and small intestine. Ghrelin is mainly degraded by the kidney [9]. In addition to stomach and small intestine, small amount of ghrelin has also been detected in hypothalamic arcuate nucleus and many other tissues. GHS-R1a is expressed by neurons in the arcuate nucleus and the ventromedial hypothalamus. Ghrelin is a circulating hunger hormone and is considered the counter regulatory hormone for leptin. Ghrelin levels increase before meal and decrease after meals. Ghrelin and synthetic ghrelin analogues increase food intake by an action exerted at the level of the hypothalamus. They activate cells in the arcuate nucleus that include the orexigenic NPY neurons [10]. Ghrelinresponsiveness of these neurons is both leptin- and insulinsensitive [11]. Ghrelin also activates the mesolimbic cholinergic/dopaminergic pathways, a circuit that communicates the hedonic and reinforcing aspects of natural rewards, such as food and ethanol [12]. Most studies to date have focused on the effects of pharmacological doses of ghrelin and its analogues in human and animal models. These effects include stimulation of GH-releasing activity, stimulation of ACTH release, inhibition of gonadotropin secretion, stimulation of appetite and positive energy balance, changes in gastric motility and acid secretion, protective effects against gastric mucosal injury, and modulation of pancreatic function and glucose metabolism enhanced cardiovascular performance via GH-growth-like factor (IGF-I) axis, as well as modulation of immune system and bone biology [9, 13, 14]. Three distinguished ghrelin gene products, that is, acyl ghrelin, des-acyl ghrelin and obestatin, have been identified. Acyl ghrelin was identified as the endogenous cognate ligand

International Journal of Peptides for the GHS-R1a [8]. The second endogenous cognate ligand for GHS-R, des-Gln14-ghrelin, another novel 27-amino acid peptide, is created by alternative splicing of the ghrelin gene and constitutes one fifth of ghrelin immunoreactivity of the rat stomach [15]. Acyl ghrelin increases meal size [16, 17]. Acyl ghrelin and GHRH are both endogenous GH-releasing peptides. GHRH acts on the GHRH receptor, distinct from GHS-R1a, to activate adenylate cyclase and to increase intracellular cAMP, which serves as a second messenger to activate subsequent signaling cascade [9]. In contrast, des-acyl ghrelin, lacking O-n-octanoylation at serine 3, is also produced in the stomach and remains the major molecular form secreted into the circulation. Des-acyl ghrelin has been shown to actively participate in food intake [18], gut motility [19], body size development [19, 20], adipogenesis [21], insulin secretion and resistance [22], and to increase tension of guinea pig papillary muscle ex vivo [23], and cell proliferation and survival in vitro [24, 25]. Des-acyl ghrelin was secreted in a highly regulated manner in response to food deprivation in mice [26]. Intracerebroventricular (icv) administration of rat des-acyl ghrelin to rats or mice stimulated feeding and induced the expression of Fos, a marker of neuronal activation, in orexin-expressing neurons of the lateral hypothalamic area. Peripheral administration of des-acyl ghrelin to rats or mice did not affect feeding. Des-acyl ghrelin increased the intracellular calcium concentrations in isolated orexin neurons. Central des-acyl ghrelin may activate orexin-expressing neurons, perhaps functioning in feeding regulation through interactions with a target protein distinct from the GHSR1a [27]. The third ghrelin gene product, obestatin, a novel 23-amino acid peptide identified from rat stomach, was derived from the mammalian prepro-ghrelin gene, which also encodes ghrelin, by comparative genomic analyses [28]. It was originally projected that obestatin binds to an orphan G protein-coupled receptor, termed GPR39, to inhibit food intake [28]. Obestatin induces early-response gene expression in stomach, intestine, white adipose tissue, liver, and kidney, suggesting its role as a gastrointestinal and metabolic hormone [29]. Obestatin activates neurons in several brain regions. Icv injection of obestatin inhibits thirst and vasopressin secretion, suppresses food intake, regulates sleep, decreases anxiety, and improves memory. Coupled with the ability of obestatin to activate cortical neurons and to stimulate the proliferation and downstream signaling of human retinal pigment epithelial cells, these findings underscore diverse functions of obestatin [30]. Disturbance of circulating ghrelin and obestatin may have a role in the pathogenesis of cachexia. Obestatin levels were significantly increased in cardiac patients with cachexia than patients without cachexia and healthy controls [31]. Serum and saliva ghrelin and obestatin levels were elevated in 24 hemodialysis patients compared with age-matched healthy controls [32]. Obestatin manifested various biological functions, such as improving memory performance, causing anxiolytic effects [33], inhibiting thirst in rats [34], activating cortical neurons [35], stimulating proliferation of retinal pigment epithelial cells in vitro [36], and profoundly influencing sleep [37, 38].

International Journal of Peptides Serine-3 of ghrelin, which is acylated with an eightcarbon fatty acid, octanoate, is inextricably required for the multifaceted endocrine functions of acyl ghrelin. Despite the crucial role for octanoylation in the physiology of ghrelin, the lipid transferase that mediates this novel modification had remained unknown until recently. In 2008, ghrelin Oacyltransferase (GOAT), attaching octanoate to serine-3 of ghrelin, was identified and characterized by two independent research groups [39, 40]. Ghrelin seems to be the sole substrate for GOAT. GOAT is located in the endoplasmic reticulum, and the presumed donor for octanoylation is octanoyl-CoA. Expression of GOAT was demonstrated to be limited to the gastrointestinal tract, intestine, testis [39], and the pancreas [40], the major ghrelin-secreting tissues. The discovery of GOAT, an enzyme specific for octanylation of ghrelin, may hold the promise of answering some major questions about the unknown but important physiological roles of ghrelin [41].

4. Ghrelin and Body Composition Muscle mass is important for physical fitness and metabolic regulation. Human observational study suggested that fasting plasma ghrelin concentration is related to skeletal muscle mass in healthy adults. After accounting for other covariates, total body skeletal mass was a significant negative predictor of ghrelin concentrations [42]. Effects of an oral ghrelin mimetic on body composition and clinical outcomes in 65 healthy older adults were analyzed. Over 12 months, the ghrelin mimetic MK-667 enhanced growth hormone secretion, significantly increased fat-free mass, and was generally well tolerated [43]. In a longitudinal study, relationship between body composition and plasma ghrelin levels was investigated in a group of end-stage renal disease (ESRD) adult patients. Changes in plasma ghrelin during 12 months of peritoneal dialysis treatment are associated with changes in body composition. Markedly elevated plasma ghrelin levels are found in advanced renal failure and correlate with fat mass [44]. Ghrelin regulates fat distribution and energy metabolism in lean tissues such as liver and muscles. In liver, ghrelin induced a lipogenic and glucogenic pattern of gene expression and increased triglyceride content while reducing activated (phosphorylated) stimulator of fatty acid oxidation, AMP-activated protein kinase (AMPK), with unchanged mitochondrial oxidative enzyme activities. In contrast, triglyceride content was reduced after ghrelin administration in mixed (gastrocnemius) and unchanged in oxidative (soleus) muscle. In mixed muscle, ghrelin increased mitochondrial oxidative enzyme activities independent of changes in expression of fat metabolism genes and phosphorylated AMPK. Expression of peroxisome proliferatoractivated receptor-γ (PPAR-γ), the activation of which reduces muscle fat content, was selectively increased in mixed muscle where it paralleled changes in oxidative capacities [45]. Thus ghrelin induces tissue-specific changes in mitochondrial and lipid metabolism gene expression and favors triglyceride deposition in liver over skeletal muscle. These novel effects of ghrelin in the regulation of lean tissue fat

3 distribution and metabolism could contribute to metabolic adaptation to caloric restriction and loss of body fat.

5. Ghrelin and Inflammation Chronic inflammation modulates ghrelin levels in humans and rats [46]. In rat model of adjuvant-induced arthritis, there is a compensatory variation of ghrelin levels that relates to body weight adjustments [46]. Recovery of ghrelin levels in the latter stage suggests an adaptive response and may represent a compensatory mechanism under catabolic conditions. Similar results were observed in patients with rheumatoid arthritis [46]. Recent studies also suggest that prostacyclin signaling regulates circulating ghrelin during acute inflammation. Madison et al. have investigated the mechanism of the regulation of ghrelin by inflammation. Ghrelin levels fall in states of acute inflammation brought about by injection of bacterial lipopolysaccharide (LPS). They demonstrate that IL-1β receptor is expressed within the gastric mucosa, but is not expressed by ghrelin cells. The prostacyclin receptor was also expressed in the gastric mucosa, and the majority of ghrelin-producing cells were found to co-express this receptor. Mice with genetic deletion of the IL-1β receptor do not suppress circulating ghrelin levels with LPS administration [47]. Collectively, their data support the notion that inflammation-induced decreases in ghrelin are likely due to the action of IL-1β on cells within the gastric mucosa that in turn produce prostacyclin as a second messenger. These data provide further support for the potential role of ghrelin as a therapeutic agent in acute and chronic inflammatory diseases.

6. Ghrelin and CKD Conflicting results of circulating ghrelin levels in CKD have been presented. Elevated plasma ghrelin levels were observed in adult dialysis patients than those of age-matched controls ´ [48]. Szczepanska et al. reported that plasma ghrelin levels were similar in CKD children on dialysis compared with children on conservative treatment and healthy controls [49]. In another study, adult hemodialysis patients showed similar serum ghrelin levels whereas peritoneal dialysis patients exhibited significantly lower serum ghrelin concentrations than predialysis CKD patients [50]. Multiple confounding factors may contribute to these seemingly contradicting findings. The two major forms of circulating ghrelin are acylated (